Antiarrhythmic Drugs

Mechanisms of Arrhythmias (Background)

1. Abnormal automaticity - Ectopic pacemakers outside the SA node fire at inappropriate rates. Most antiarrhythmics suppress this by blocking Na+ or Ca2+ channels, decreasing the slope of phase 4 (diastolic) depolarization and/or raising the threshold to a less negative voltage.
2. Reentry - The most common cause of arrhythmias. A unidirectional block (from myocardial injury or prolonged refractory period) creates a short-circuit pathway that re-excites cardiac muscle. Class I drugs prevent reentry by slowing conduction; Class III drugs prevent it by increasing the refractory period, both converting a unidirectional block into a bidirectional block.

Vaughan-Williams Classification

CLASS I - Sodium Channel Blockers

Class IA - Na+ Block + K+ Block (Intermediate Dissociation)

• Block Na+ channels (open-state dependent) - slow phase 0 depolarization
• Also block K+ channels, prolonging phase 3 repolarization
• Net effect: slow conduction velocity AND prolong action potential duration (APD) / QT interval
• Moderate rate of dissociation from Na+ channels

• Atrial fibrillation / flutter (rhythm conversion and maintenance)
• Ventricular tachycardia
• Paroxysmal SVT (quinidine, procainamide)
• WPW syndrome (slows accessory pathway conduction)

• QT prolongation → torsades de pointes (life-threatening)
• Pro-arrhythmia, ventricular arrhythmias
• Acute heart failure, syncope, dizziness
• Quinidine specific: cinchonism (tinnitus, headache, visual disturbances), hemolytic anemia, esophagitis, thrombocytopenia, diarrhea
• Procainamide specific: drug-induced lupus-like syndrome (anti-histone antibodies), hypotension (especially IV)
• Disopyramide specific: strong anticholinergic effects (dry mouth, urinary retention, blurred vision, constipation) - avoid in elderly; potent negative inotrope - avoid in heart failure

Class IB - Na+ Channel Block (Fast Dissociation)

• Block Na+ channels with preference for inactivated state (ischemic/depolarized tissue)
• Shorten phase 3 repolarization (shorten APD)
• Very rapid dissociation from channels - minimal effect at normal heart rates
• Little effect on normal tissue; selectively suppress ectopic activity in ischemic tissue

• Lidocaine: IV treatment of acute ventricular arrhythmias, especially post-MI and digitalis-induced VT; first-line IV agent for acute VT/VF
• Mexiletine: Oral equivalent of lidocaine; chronic ventricular arrhythmias; also used in long QT syndrome (type 3) and myotonic dystrophy
• Phenytoin: Digitalis-induced arrhythmias (historical use)

• CNS toxicity (lidocaine): dizziness, tremor, ataxia, paresthesia, confusion, seizures (dose-dependent)
• Worsening ventricular arrhythmias
• Liver failure (mexiletine)
• Mexiletine: nausea, vomiting, dyspepsia, dysphagia

Class IC - Na+ Channel Block (Slow Dissociation - Marked)

• Most potent Na+ channel blockers - markedly slow phase 0 depolarization and conduction velocity
• Slow dissociation from Na+ channels → use-dependent block accumulates
• Minimal effect on repolarization
• Propafenone: also has mild beta-blocking and Ca2+ channel blocking properties

• Atrial fibrillation / flutter (rhythm control) - well tolerated in patients with structurally normal hearts
• "Pill-in-the-pocket" approach for paroxysmal AF
• Propafenone: also SVT, accessory pathway tachycardias (WPW)

• Bradycardia, QT prolongation, worsening ventricular arrhythmias (pro-arrhythmic)
• Hypotension, heart failure, syncope
• Tremor, headache, visual disturbances, constipation
• CAST Trial Warning: Flecainide/encainide increased mortality in post-MI patients with asymptomatic ventricular ectopy - Class IC drugs are CONTRAINDICATED in structural heart disease (post-MI, LVH, heart failure)
• Propafenone: bronchospasm (beta-blocking effect), hepatic failure, agranulocytosis, anemia, edema

CLASS II - Beta-Adrenergic Blockers

• Competitively block beta-1 (and beta-2 for non-selective agents) adrenergic receptors
• Inhibit phase 4 (spontaneous diastolic) depolarization in SA and AV nodes
• Decrease SA node automaticity → reduce heart rate
• Slow AV nodal conduction → increase PR interval, reduce ventricular rate in AF/flutter
• Reduce intracellular Ca2+ overload
• Inhibit afterdepolarization-mediated automaticity
• Increase energy required to fibrillate the heart in ischemic tissue

• Atrial fibrillation/flutter (rate control)
• SVT - slow or terminate AVNRT
• Prevention of post-MI arrhythmias (proven mortality benefit)
• Ventricular arrhythmias associated with sympathetic excess (exercise-induced, stress-induced)
• Catecholamine-sensitive VT (e.g., CPVT)
• Thyrotoxicosis-related arrhythmias
• Long QT syndrome (beta-blocker is first-line for LQT1 and LQT2)
• Electrical storm (propranolol specifically shown superior to metoprolol)

• Bradycardia, heart block
• Hypotension
• Worsening heart failure (acute decompensation)
• Bronchospasm (especially non-selective agents - avoid in asthma)
• Masking of hypoglycemia symptoms (in diabetics)
• Fatigue, sleep disturbances, depression, sexual dysfunction
• Cold extremities (peripheral vasoconstriction)
• Hyperlipidemia, hypertriglyceridemia

• Caution in asthma/COPD (use cardioselective agents if necessary)
• Avoid in high-degree AV block without pacemaker
• Do NOT abruptly discontinue - withdrawal syndrome (rebound tachycardia, angina, possible MI) due to beta-receptor up-regulation

CLASS III - Potassium Channel Blockers

• Block delayed rectifier K+ channels → prolong phase 3 repolarization
• Widen action potential and prolong effective refractory period
• Prolong QT interval
• Prevent reentry by increasing the refractory period

• Atrial fibrillation/flutter (rhythm control)
• Ventricular tachycardia/fibrillation
• Amiodarone: Most effective antiarrhythmic overall; used for both AF and life-threatening VT/VF, especially with structural heart disease; safe in heart failure
• Dofetilide/Ibutilide: AF/flutter cardioversion and maintenance
• Sotalol: AF maintenance, ventricular arrhythmias (also has Class II properties)

• QT prolongation → torsades de pointes (paradoxically most with dofetilide/ibutilide/sotalol; less with amiodarone)
• Worsening ventricular arrhythmias

• Pulmonary toxicity (pneumonitis, fibrosis) - most serious
• Hepatic failure, transaminitis
• Thyroid dysfunction (hypo- and hyperthyroidism) - contains iodine
• Peripheral neuropathy, paresthesia
• Corneal microdeposits, optic neuritis (visual disturbances)
• Blue-gray skin discoloration (with prolonged use)
• Bradycardia, hypotension
• Drug interactions via CYP450 (inhibits warfarin metabolism, raises digoxin levels)

• Monitor thyroid, liver, and pulmonary function with amiodarone
• Amiodarone has extremely long half-life (~40-55 days) - effects persist months after discontinuation
• Sotalol/dofetilide: dose-adjust in renal impairment; monitor QTc

CLASS IV - Calcium Channel Blockers (Non-Dihydropyridines)

• Block L-type Ca2+ channels in SA and AV nodes
• Inhibit phase 0 of the action potential in SA/AV nodal tissue (which is Ca2+-dependent, unlike fast-response tissue)
• Slow SA node automaticity and AV node conduction
• Prolong AV nodal refractory period

• Rate control in atrial fibrillation/flutter
• Termination of AVNRT (adenosine preferred first)
• Prevention of AVNRT recurrence
• Verapamil: effective in some idiopathic left VT (verapamil-sensitive VT)
• Inappropriate sinus tachycardia

• Bradycardia, AV heart block
• Acute heart failure / negative inotropic effect (more so with verapamil)
• Peripheral edema, hypotension, dizziness
• Constipation (especially verapamil)
• Gingival hyperplasia (verapamil)
• Gynecomastia, sexual dysfunction

• Avoid verapamil + beta-blocker combination (risk of severe bradycardia/block)
• Contraindicated in WPW with AF (can increase accessory pathway conduction and cause VF)
• Avoid in severe LV dysfunction

Other Antiarrhythmic Agents (Not Formally Classified)

PROPRANOLOL - Detailed Focus

Classification

Antiarrhythmic Effects and MOA

1. Beta-1 receptor blockade at SA node - decreases the slope of phase 4 diastolic depolarization, reducing SA node automaticity and heart rate
2. Beta-1 receptor blockade at AV node - slows AV nodal conduction velocity, prolongs AV nodal refractory period → increases PR interval, limits ventricular rate in AF/flutter
3. Suppression of catecholamine-driven arrhythmias - blocks adrenergic effects on the heart. Beta blockade reduces intracellular Ca2+ overload and inhibits afterdepolarization-mediated automaticity (both DADs and EADs triggered by sympathetic excess)
4. Non-selective beta-2 blockade - prevents epinephrine-induced hypokalemia (mediated via beta-2 receptors), which can be pro-arrhythmic in ischemic states. Propranolol's non-selectivity is actually an advantage here over cardioselective agents
5. Anti-ischemic effect - in acutely ischemic tissue, propranolol increases the energy required to fibrillate the heart, providing additional protection against VF
6. Membrane-stabilizing effect - at high concentrations, propranolol has a direct Na+ channel blocking action (local anesthetic/quinidine-like effect), though this is not thought to be clinically significant at therapeutic doses

Therapeutic Uses (Antiarrhythmic)

• Atrial fibrillation/flutter - ventricular rate control
• Paroxysmal SVT (AVNRT, AVRT) - slows or terminates by blocking AV nodal conduction
• Post-myocardial infarction arrhythmias - beta-blockers are the standard of care for preventing ventricular arrhythmias after MI; reduce sudden cardiac death (proven mortality benefit)
• Electrical storm (refractory VT/VF) - non-selective propranolol has shown superiority over metoprolol in one key study, highlighting the benefit of beta-2 blockade in preventing epinephrine-induced hypokalemia
• Exercise-induced/stress-induced ventricular arrhythmias - catecholamine-sensitive tachycardias
• Catecholaminergic polymorphic VT (CPVT) - propranolol is first-line
• Long QT syndrome (LQT1, LQT2) - beta-blockade is the primary medical treatment
• Thyrotoxicosis - controls tachyarrhythmias caused by excess thyroid-driven adrenergic sensitization
• Hypertrophic obstructive cardiomyopathy - controls outflow tract obstruction and associated arrhythmias
• Arrhythmias associated with pheochromocytoma - ONLY after alpha-blockade is established first

Other Therapeutic Uses (Non-Antiarrhythmic)

• Hypertension (decreases cardiac output; inhibits renin release)
• Angina pectoris (reduces O2 demand)
• Migraine prophylaxis
• Essential tremor
• Portal hypertension / variceal bleeding prophylaxis
• Anxiety / situational performance anxiety
• Infantile hemangiomas (topical/oral)

Precautions and Contraindications

• Propranolol's non-selectivity (beta-1 + beta-2) makes it uniquely effective in catecholamine excess states (pheochromocytoma crisis post-alpha-block, thyroid storm, CPVT, electrical storm) but also makes it riskier in asthmatics and diabetics compared to cardioselective agents like metoprolol
• Among antiarrhythmics, propranolol and beta-blockers as a class have the best survival data post-MI
• In heart failure with AF, amiodarone or dofetilide are preferred for rhythm control; beta-blockers remain useful for rate control in chronic stable HF
• Class IC agents (flecainide, propafenone) are contraindicated where propranolol is often safe - patients with structural heart disease